Hypercholesterolemia can induce monocytes to migrate into the arterial wall and mature into foam cells or tissue macrophages that accumulate fatty material, including cholesterol esters. For example, continued creation of foam cells thickens the inner lining of medium and large arteries, thereby forming atherosclerotic plaques or lesions containing cholesterol, smooth muscle cells, and connective tissue cells. Affected arteries lose elasticity and become narrowed or obstructed by the plaques. These events are the hallmark of the disease atherosclerosis. Furthermore, atherosclerotic plaques may collect calcium, become brittle, and even rupture, triggering the formation of a blood clot or thrombus capable of occluding an artery and causing a stroke or a heart attack. In addition to atherosclerosis, hypercholesterolemia plays a role in peripheral vascular diseases of small arteries, veins, and lymphatics. Thus, hypercholesterolemia may also affect the arms, legs, kidneys, and other vital organs in addition to the heart and brain.
Cholesterol is transported in blood in particles called lipoproteins, which include low-density lipoproteins (LDL). Lipoproteins also contain cholesterol and are necessary for foam cell formation.
Lipoxygenases are enzymes that catalyze the oxidation of polyunsaturated fatty acids and esters thereof, including those found in low-density lipoproteins. For example, the enzyme 15-lipoxygenase (15-LO) oxidizes esterified polyenoic fatty acids. 15-LO has been implicated in inflammatory disorders and in the origin and recruitment of foam cells. In addition to modifying lipoproteins involved in the formation of foam cells, 15-LO also mediates an inflammatory reaction in the atherosclerotic lesion In human monocytes, 15-LO is induced by the cytokine IL-4.
Inhibitors of 15-LO are therefore useful to prevent and treat diseases with an inflammatory component such as asthma, psoriasis, osteoarthritis, rheumatoid arthritis, colorectal cancer, and atherosclerosis. For example, it has been shown that treatment with an inhibitor of 15-LO suppressed atherogenesis, or the production of atheroma, a fatty degeneration of the arterial wall, in rabbits fed a high-fat diet
A chief object of this invention is to provide new 1,2,4-trisubstituted benzenes that are potent inhibitors of 15-LO.